Role of the microsomal fad-containing monooxygenase in the liver toxicity of thioacetamide S-oxide

Chieli, Elisabetta; Malvaldi, Gino

doi:10.1016/0300-483x(84)90154-9

Cited by 122 publications

(70 citation statements)

References 14 publications

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“…Together, our results suggest the hepatoprotective effects of SLE and DDB are not likely resourced from the direct influence on the metabolic bioactivation of TAA. In combination with our previous report (Hao et al, 2011), our results provide novel evidence supporting the previous assumption that TAA hepatotoxicity is mainly caused by TAA's reactive metabolites on covalently modifying macromolecules (Chieli and Malvaldi, 1984). However, it is important to note that the TAA chronic intoxication leads to a differential regulating mode between P450s and FIG.…”

Section: Discussionsupporting

confidence: 90%

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Xie¹,

Wang²,

Wang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

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Section: Discussionsupporting

confidence: 90%

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Xie¹,

Wang²,

Wang³

et al. 2012

Drug Metab Dispos

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“…Thioacetamide and thiobenzamide are potent liver toxicants (Hunter et al, 1977;Hanzlik et al, 1980;Grossman et al, 1991), and the hepatotoxicity appears primarily due to FMO-mediated S-oxygenation to sulfines and sulfenes (Cashman & Hanzlik, 1981;Dyroff & Neal, 1983;Chieli & Malvaldi, 1984;Ziegler, 1984;Ruse & Waring, 1991;.…”

Section: Role Of Flavin-containing Monooxygenase In Metabolism Of S-cmentioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

503

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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“…It undergoes extensive metabolism to acetamide and thioacetamide S-dioxide by the mixed function oxidase system [68]. The thioacetamide S-dioxide is a highly reactive compound [69,70].…”

Section: Main Hepatotoxic Agents Used In Hepatoprotective Studiesmentioning

confidence: 99%

Hepatoprotective Effects of Mushrooms

et al. 2013

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Abstract:The particular characteristics of growth and development of mushrooms in nature result in the accumulation of a variety of secondary metabolites such as phenolic compounds, terpenes and steroids and essential cell wall components such as polysaccharides, β-glucans and proteins, several of them with biological activities. The present article outlines and discusses the available information about the protective effects of mushroom extracts against liver damage induced by exogenous compounds. Among mushrooms, Ganoderma lucidum is indubitably the most widely studied species. In this review, however, emphasis was given to studies using other mushrooms, especially those presenting efforts of attributing hepatoprotective activities to specific chemical components usually present in the mushroom extracts.

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Role of the microsomal fad-containing monooxygenase in the liver toxicity of thioacetamide S-oxide

Cited by 122 publications

References 14 publications

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Hepatoprotective Effects of Mushrooms

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